Abstract

Although gene-environment interactions have been investigated for many years to understand people’s susceptibility to autoimmune diseases or cancer, a role for environmental factors in modulating alloimmune responses and transplant outcomes is only now beginning to emerge. New data suggest that diet, hyperlipidemia, pollutants, commensal microbes, and pathogenic infections can all affect T cell activation, differentiation, and the kinetics of graft rejection. These observations reveal opportunities for novel therapeutic interventions to improve graft outcomes as well as for noninvasive biomarker discovery to predict or diagnose graft deterioration before it becomes irreversible. In this Review, we will focus on the impact of these environmental factors on immune function and, when known, on alloimmune function, as well as on transplant fate.

Figure 1

High-salt diet may stimulate macrophages to differentiate into classical macrophages (M1), potentiating their effector function through NFAT5 activation and increasing the immune response against Leishmania infection. In a murine model of wound healing, high salt inhibits M2 differentiation through inhibition of mTOR/AKT signaling, leading to delayed wound healing. In adaptive immunity, high salt may potentiate Th17 cell differentiation and exacerbate disease in the experimental autoimmune encephalomyelitis (EAE) model. In a murine model of cardiac transplantation, high-salt diet is deleterious to immune regulation and precipitates rejection by reducing the proportion of Tregs via SGK1 activation and consequent FoxO1/FoxO3a phosphorylation.